Narcoleptic
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Narcolepsy is a chronic
neurological disorder Neurological disorders represent a complex array of medical conditions that fundamentally disrupt the functioning of the nervous system. These disorders affect the brain, spinal cord, and nerve networks, presenting unique diagnosis, treatment, and ...
that impairs the ability to regulate sleep–wake cycles, and specifically impacts REM (rapid eye movement) sleep. The symptoms of narcolepsy include excessive daytime sleepiness (EDS), sleep-related
hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...
s,
sleep paralysis Sleep paralysis is a state, during waking up or falling asleep, in which a person is conscious but in a complete state of full-body paralysis. During an episode, the person may hallucinate (hear, feel, or see things that are not there), wh ...
, disturbed nocturnal sleep (DNS), and
cataplexy Cataplexy is a sudden and transient episode of muscle weakness accompanied by full conscious awareness, typically triggered by emotions such as laughing, crying, or terror. Cataplexy is the first symptom to appear in about 10% of cases of narcol ...
. People with narcolepsy typically have poor quality of sleep. There are two recognized forms of narcolepsy, narcolepsy type 1 and type 2. Narcolepsy type 1 (NT1) can be clinically characterized by symptoms of EDS and cataplexy, and/or will have
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
(CSF)
orexin Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy, type 1, in which the individual experiences brief loss ...
levels of less than 110 pg/ml. Cataplexy are transient episodes of aberrant tone, most typically loss of tone, that can be associated with strong emotion. In pediatric-onset narcolepsy, active motor phenomena are not uncommon. Cataplexy may be mistaken for syncope,
tics A tic is a sudden and repetitive motor movement or vocalization that is not rhythmic and involves discrete muscle groups. Tics are typically brief and may resemble a normal behavioral characteristic or gesture. Tics can be invisible to the obs ...
, or
seizure A seizure is a sudden, brief disruption of brain activity caused by abnormal, excessive, or synchronous neuronal firing. Depending on the regions of the brain involved, seizures can lead to changes in movement, sensation, behavior, awareness, o ...
s. Narcolepsy type 2 (NT2) does not have features of cataplexy, and CSF orexin levels are normal. Sleep-related
hallucinations A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...
, also known as
hypnogogic Hypnagogia is the transitional state from wakefulness to sleep, also defined as the waning state of consciousness during the onset of sleep. Its corresponding state is '' hypnopompia'' sleep to wakefulness. Mental phenomena that may occur duri ...
(going to sleep) and
hypnopompic Hypnopompia (also known as hypnopompic state) is the state of consciousness leading out of sleep, a term coined by the psychical researcher Frederic William Henry Myers, Frederic Myers. Its mirror is the hypnagogic state at sleep onset; though ...
(on awakening), are vivid hallucinations that can be auditory,
visual The visual system is the physiological basis of visual perception (the ability to detect and process light). The system detects, transduces and interprets information concerning light within the visible range to construct an image and buil ...
, or
tactile Tactile may refer to: * Tactile, related to the sense of touch * Haptics (disambiguation) * Tactile (device), a text-to-braille translation device * Tactile paving See also * Tangibility, in law * Somatosensory system The somatosensory s ...
and may occur independent of or in combination with an inability to move (
sleep paralysis Sleep paralysis is a state, during waking up or falling asleep, in which a person is conscious but in a complete state of full-body paralysis. During an episode, the person may hallucinate (hear, feel, or see things that are not there), wh ...
). Narcolepsy is a clinical syndrome of hypothalamic disorder, but the exact cause of narcolepsy is unknown, with potentially several causes. A leading consideration for the cause of narcolepsy type 1 is that it is an
autoimmune disorder An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
. Proposed pathophysiology as an autoimmune disease suggest antigen presentation by DQ0602 to specific
CD4+ T cells The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considere ...
resulting in
CD8+ T-cell A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular p ...
activation and consequent injury to orexin producing neurons. Familial trends of narcolepsy are suggested to be higher than previously appreciated. Familial risk of narcolepsy among first-degree relatives is high. Relative risk for narcolepsy in a first-degree relative has been reported to be 361.8. However, there is a spectrum of symptoms found in this study, including asymptomatic abnormal sleep test findings to significantly symptomatic. The autoimmune process is thought to be triggered in genetically susceptible individuals by an immune-provoking experience, such as infection with H1N1 influenza. Secondary narcolepsy can occur as a consequence of another neurological disorder. Secondary narcolepsy can be seen in some individuals with
traumatic brain injury A traumatic brain injury (TBI), also known as an intracranial injury, is an injury to the brain caused by an external force. TBI can be classified based on severity ranging from mild traumatic brain injury (mTBI/concussion) to severe traumati ...
, tumors,
Prader–Willi syndrome Prader–Willi syndrome (PWS) is a rare genetic disorder caused by a loss of function of specific genes on chromosome 15. In newborns, symptoms include hypotonia, weak muscles, poor feeding, and slow development. Beginning in childhood, those ...
or other diseases affecting the parts of the brain that regulate wakefulness or
REM sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals (including humans) and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the s ...
. Diagnosis is typically based on the symptoms and
sleep studies A sleep study is a test that records the activity of the body during sleep. There are five main types of sleep studies that use different methods to test for different sleep characteristics and disorders. These include simple sleep studies, polysom ...
, after excluding alternative causes of EDS. EDS can also be caused by other
sleep disorder A sleep disorder, or somnipathy, is a medical disorder affecting an individual's sleep patterns, sometimes impacting physical, mental, social, and emotional functioning. Polysomnography and actigraphy are tests commonly ordered for diagnosing sle ...
s such as insufficient sleep syndrome,
sleep apnea Sleep apnea (sleep apnoea or sleep apnœa in British English) is a sleep-related breathing disorder in which repetitive Apnea, pauses in breathing, periods of shallow breathing, or collapse of the upper airway during sleep results in poor vent ...
,
major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...
,
anemia Anemia (also spelt anaemia in British English) is a blood disorder in which the blood has a reduced ability to carry oxygen. This can be due to a lower than normal number of red blood cells, a reduction in the amount of hemoglobin availabl ...
,
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...
, and drinking
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
. While there is no cure, behavioral strategies, lifestyle changes, social support, and medications may help. Lifestyle and behavioral strategies can include identifying and avoiding or desensitizing emotional triggers for cataplexy, dietary strategies that may reduce sleep-inducing foods and drinks, scheduled or strategic naps, and maintaining a regular sleep-wake schedule. Social support, social networks, and social integration are resources that may lie in the communities related to living with narcolepsy. Medications used to treat narcolepsy primarily target EDS and/or cataplexy. These medications include alerting agents (e.g.,
modafinil Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant and wakefulness-promoting agent, eugeroic (wakefulness promoter) medication used primarily to treat narcolepsy, a sleep disorder characteri ...
,
armodafinil Armodafinil, sold under the brand name Nuvigil, is a wakefulness-promoting medication which is used to treat excessive daytime sleepiness associated with obstructive sleep apnea, narcolepsy, and shift work disorder. It is also used off-label ...
,
pitolisant Pitolisant, sold under the brand name Wakix among others, is a medication used for the treatment of excessive daytime sleepiness in adults with narcolepsy. It is an inverse agonist of the histamine H3 receptor. It represents the first commerc ...
,
solriamfetol Solriamfetol, sold under the brand name Sunosi, is a wakefulness-promoting medication used in the treatment of excessive sleepiness related to narcolepsy and sleep apnea. It is taken by mouth. Common side effects of solriamfetol include hea ...
), oxybate medications (e.g., twice nightly
sodium oxybate Sodium is a chemical element; it has symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable isotope ...
, twice nightly mixed oxybate salts, and once nightly
extended-release Modified-release dosage is a mechanism that (in contrast to immediate-release dosage) delivers a drug with a delay after its administration (delayed-release dosage) or for a prolonged period of time (extended-release R, XR, XLdosage) or to a spe ...
sodium oxybate), and other
stimulants Stimulants (also known as central nervous system stimulants, or psychostimulants, or colloquially as uppers) are a class of drugs that increase alertness. They are used for various purposes, such as enhancing attention, motivation, cognitio ...
(e.g.,
methylphenidate Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...
,
amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...
). There is also the use of
antidepressants Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include dry mouth, weight gain, dizziness, headaches, akathisia, sexu ...
such as
tricyclic antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains ...
s,
selective serotonin reuptake inhibitor Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by blo ...
s (SSRIs), and serotonin–norepinephrine reuptake inhibitors (SNRIs) for the treatment of cataplexy. Estimates of frequency range from 0.2 to 600 per 100,000 people in various countries. The condition often begins in childhood, with males and females being affected equally. Untreated narcolepsy increases the risk of
motor vehicle collisions A traffic collision, also known as a motor vehicle collision, or car crash, occurs when a vehicle collides with another vehicle, pedestrian, animal, road debris, or other moving or stationary obstruction, such as a tree, pole or building. Tr ...
and falls. Narcolepsy generally occurs anytime between early childhood and 50 years of age, and most commonly between 15 and 36 years of age. However, it may also rarely appear at any time outside of this range.


Signs and symptoms

There are two main characteristics of narcolepsy: excessive daytime sleepiness and abnormal
REM sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals (including humans) and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the s ...
. Excessive daytime sleepiness occurs even after adequate night time sleep. A person with narcolepsy is likely to become drowsy or fall asleep, often at inappropriate or undesired times and places, or just be very tired throughout the day. Narcoleptics may not be able to experience the amount of restorative deep sleep that healthy people experience due to abnormal REM regulation – they are not "oversleeping." Narcoleptics typically have higher REM sleep density than non-narcoleptics, but also experience more REM sleep without
atonia This glossary of medical terms is a list of definitions about medicine, its sub-disciplines, and related fields. A * Aarskog–Scott syndrome – (AAS) A rare, inherited (X-linked) disease characterized by short stature, facial abnormalities, ...
. Many narcoleptics have sufficient REM sleep, but do not feel refreshed or alert throughout the day. This can feel like living their entire lives in a constant state of sleep deprivation. Excessive sleepiness can vary in severity and appears most commonly during monotonous situations that require little interaction. Daytime naps may occur with little warning and may be physically irresistible. These naps can occur several times a day. They are typically refreshing, but only for a brief period. Vivid dreams may be experienced regularly, even during short naps. Drowsiness may persist for prolonged periods or remain constant. Additionally, nighttime sleep may be fragmented, with frequent awakenings. A second prominent symptom of narcolepsy is abnormal REM sleep. Narcoleptics are unique in that they enter into the REM phase of sleep at the beginning of sleep, even when sleeping during the day. The classic symptoms of the disorder, often referred to as the "tetrad of narcolepsy", are
cataplexy Cataplexy is a sudden and transient episode of muscle weakness accompanied by full conscious awareness, typically triggered by emotions such as laughing, crying, or terror. Cataplexy is the first symptom to appear in about 10% of cases of narcol ...
,
sleep paralysis Sleep paralysis is a state, during waking up or falling asleep, in which a person is conscious but in a complete state of full-body paralysis. During an episode, the person may hallucinate (hear, feel, or see things that are not there), wh ...
, hypnagogic hallucinations, and excessive daytime sleepiness. Other symptoms may include automatic behaviors and night-time wakefulness. These symptoms may not occur in all people with narcolepsy. * An episodic loss of muscle function, known as cataplexy, ranging from slight weakness such as limpness at the neck or knees, sagging facial muscles, weakness at the knees often referred to as "knee buckling", or inability to speak clearly, to a complete body collapse. Episodes may be triggered by sudden emotional reactions such as
laughter Laughter is a pleasant physical reaction and emotion consisting usually of rhythmical, usually audible contractions of the diaphragm and other parts of the respiratory system. It is a response to certain external or internal stimuli. Laug ...
,
anger Anger, also known as wrath ( ; ) or rage (emotion), rage, is an intense emotional state involving a strong, uncomfortable and non-cooperative response to a perceived provocation, hurt, or threat. A person experiencing anger will often experie ...
, surprise, or
fear Fear is an unpleasant emotion that arises in response to perception, perceived dangers or threats. Fear causes physiological and psychological changes. It may produce behavioral reactions such as mounting an aggressive response or fleeing the ...
. The person remains conscious throughout the episode. In some cases, cataplexy may resemble epileptic seizures. Usually, speech is slurred and vision is impaired (double vision, inability to focus), but hearing and awareness remain normal. Cataplexy also has a severe emotional impact on narcoleptics, as it can cause extreme anxiety, fear, and avoidance of people or situations that might elicit an attack. Cataplexy is generally considered to be unique to narcolepsy and is analogous to sleep paralysis in that the usually protective paralysis mechanism occurring during sleep is inappropriately activated. The opposite of this situation (failure to activate this protective paralysis) occurs in rapid eye movement behavior disorder. * Periods of wakefulness at night. * The temporary inability to talk or move when waking (or, less often, when falling asleep), known as sleep paralysis. It may last a few seconds to minutes. This is often frightening but is not dangerous. * Vivid, often frightening, dreamlike experiences that occur while dozing or falling asleep, known as hypnagogic hallucinations. Hypnopompic hallucinations refer to the same sensations while awakening from sleep. These hallucinations may manifest in the form of visual or auditory sensations. In most cases, the first symptom of narcolepsy to appear is excessive and overwhelming daytime sleepiness. The other symptoms may begin alone or in combination months or years after the onset of the daytime naps. There are wide variations in the development, severity, and order of appearance of cataplexy, sleep paralysis, and hypnagogic hallucinations in individuals. Only about 20 to 25 percent of people with narcolepsy experience all four symptoms. The excessive daytime sleepiness generally persists throughout life, but sleep paralysis and hypnagogic hallucinations may not. Many people with narcolepsy also have
insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
for extended periods. The excessive daytime sleepiness and cataplexy often become severe enough to cause serious problems in a person's social, personal, and professional life. Normally, when an individual is awake,
brain wave Neural oscillations, or brainwaves, are rhythmic or repetitive patterns of neural activity in the central nervous system. Neural tissue can generate oscillatory activity in many ways, driven either by mechanisms within individual neurons or by ...
s show a regular rhythm. When a person first falls asleep, the brain waves become slower and less regular, which is called non-rapid eye movement ( NREM) sleep. After about an hour and a half of NREM sleep, the brain waves begin to show a more active pattern again, called
REM sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals (including humans) and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the s ...
(rapid eye movement sleep), when most remembered
dream A dream is a succession of images, ideas, emotions, and sensation (psychology), sensations that usually occur involuntarily in the mind during certain stages of sleep. Humans spend about two hours dreaming per night, and each dream lasts around ...
ing occurs. Associated with the EEG-observed waves during REM sleep, muscle atonia is present, called
REM atonia Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals (including humans) and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the s ...
. In narcolepsy, the order and length of NREM and REM sleep periods are disturbed, with REM sleep occurring at sleep onset instead of after a period of NREM sleep. Also, some aspects of REM sleep that normally occur only during sleep, like lack of muscular control, sleep paralysis, and vivid dreams, occur at other times in people with narcolepsy. For example, the lack of muscular control can occur during wakefulness in a cataplexy episode; it is said that there is an intrusion of REM atonia during wakefulness. Sleep paralysis and vivid dreams can occur while falling asleep or waking up. Simply put, the brain does not pass through the normal stages of dozing and deep sleep but goes directly into (and out of) rapid eye movement (REM) sleep. As a consequence, nighttime sleep does not include as much deep sleep, so the brain tries to "catch up" during the day, hence excessive daytime sleepiness. People with narcolepsy may visibly fall asleep at unpredictable moments (such motions as head bobbing are common). People with narcolepsy fall quickly into what appears to be very deep sleep, and they wake up suddenly and can be disoriented when they do (dizziness is a common occurrence). They have very vivid dreams, which they often remember in great detail. People with narcolepsy may dream even when they only fall asleep for a few seconds. Along with vivid dreaming, people with narcolepsy are known to have audio or visual hallucinations before falling asleep or before
waking up Sleep is a state of reduced mental and physical activity in which consciousness is altered and certain Sensory nervous system, sensory activity is inhibited. During sleep, there is a marked decrease in muscle activity and interactions with th ...
. Narcoleptics can gain excess weight; children can gain when they first develop narcolepsy; in adults, the body-mass index is about 15% above average.


Causes

The exact cause of narcolepsy is unknown, and it may be caused by several distinct factors. The mechanism involves the loss of
orexin Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy, type 1, in which the individual experiences brief loss ...
-releasing neurons within the
lateral hypothalamus The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cogni ...
(about 70,000 neurons). Some researches indicated that people with type 1 narcolepsy (narcolepsy with cataplexy) have a lower level of orexin (hypocretin), which is a chemical contributing to the regulation of wakefulness and REM sleep. It also acts as a neurotransmitter to enable nerve cells to communicate. In up to 10% of cases, there is a family history of the disorder. Family history is more common in narcolepsy with cataplexy. There is a strong link with certain genetic variants, which may make T-cells susceptible to react to the orexin-releasing neurons (
autoimmunity In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease ...
) after being stimulated by infection with H1N1 influenza. In addition to genetic factors, low levels of orexin peptides have been correlated with a history of infection, diet, contact with toxins such as pesticides, and brain injuries due to head trauma, brain tumors or strokes.


Genetics

The primary genetic factor that has been strongly implicated in the development of narcolepsy involves an area of
chromosome 6 Chromosome 6 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 6 spans nearly 171 million base pairs (the building material of DNA) and represents between 5.5 and 6% of the total DNA i ...
known as the
human leukocyte antigen The human leukocyte antigen (HLA) system is a complex of genes on chromosome 6 in humans that encode cell-surface proteins responsible for regulation of the immune system. The HLA system is also known as the human version of the major histo ...
(HLA) complex. Specific variations in HLA genes are strongly correlated with the presence of narcolepsy (HLA DQB1*06:02, frequently in combination with HLA DRB1*15:01); however, these variations are not required for the condition to occur and sometimes occur in individuals without narcolepsy. These genetic variations in the HLA complex are thought to increase the risk of an
auto-immune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an " autoimmune disease ...
response to
orexin Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy, type 1, in which the individual experiences brief loss ...
-releasing neurons in the
lateral hypothalamus The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cogni ...
. The
allele An allele is a variant of the sequence of nucleotides at a particular location, or Locus (genetics), locus, on a DNA molecule. Alleles can differ at a single position through Single-nucleotide polymorphism, single nucleotide polymorphisms (SNP), ...
HLA-DQB1*06:02 of the human gene
HLA-DQB1 Major histocompatibility complex, class II, DQ beta 1, also known as HLA-DQB1, is a human gene and also denotes the genetic locus that contains this gene. The protein encoded by this gene is one of two proteins that are required to form the DQ h ...
was reported in more than 90% of people with narcolepsy, and alleles of other HLA genes, such as HLA-DQA1*01:02, have been linked. A 2009 study found a strong association with polymorphisms in the
TRAC Trac is an open-source, web-based project management and bug tracking system. It has been adopted by a variety of organizations for use as a bug tracking system for both free and open-source software and proprietary projects and products. Tr ...
gene locus (
dbSNP The Single Nucleotide Polymorphism Database (dbSNP) is a free public archive for genetic variation within and across different species developed and hosted by the National Center for Biotechnology Information (NCBI) in collaboration with the Natio ...
IDs rs1154155, rs12587781, and rs1263646). A 2013 review article reported additional but weaker links to the loci of the genes
TNFSF4 OX40L is the ligand for OX40 (also known as CD134 or TNFRSF4) and is stably expressed on many antigen-presenting cells such as DC2s (a subtype of dendritic cells), macrophages, and activated B lymphocytes. The OX40 molecule, conversely, is pr ...
(rs7553711),
Cathepsin H Cathepsin H is a protein that in humans is encoded by the ''CTSH'' gene. The protein encoded by this gene is a cysteine cathepsin, a lysosomal cysteine protease important in the overall degradation of lysosomal proteins. It is composed of a dim ...
(rs34593439), and P2RY11-
DNMT1 DNA (cytosine-5)-methyltransferase 1 (Dnmt1) is an enzyme that catalyzes the transfer of methyl groups to specific CpG sites in DNA, a process called DNA methylation. In humans, it is encoded by the ''DNMT1'' gene In biology, the word ge ...
(rs2305795). Another
gene locus In genetics, a locus (: loci) is a specific, fixed position on a chromosome where a particular gene or genetic marker is located. Each chromosome carries many genes, with each gene occupying a different position or locus; in humans, the total numb ...
that has been associated with narcolepsy is
EIF3G Eukaryotic translation initiation factor 3 subunit G (eIF3g) is a protein that in humans is encoded by the ''EIF3G'' gene. Interactions EIF3G has been shown to interact with Band 4.1, EIF3C and EIF3A Eukaryotic translation initiation fac ...
(rs3826784).


H1N1 influenza

Type 1 narcolepsy is caused by hypocretin/orexin neuronal loss. T-cells have been demonstrated to be cross-reactive to both a particular piece of the hemagglutinin flu protein of the pandemic 2009 H1N1 and the amidated terminal ends of the secreted hypocretin peptides. Genes associated with narcolepsy mark the particular HLA heterodimer (DQ0602) involved in presentation of these antigens and modulate expression of the specific T cell receptor segments (TRAJ24 and TRBV4-2) involved in T cell receptor recognition of these antigens, suggesting causality. A link between
GlaxoSmithKline GSK plc (an acronym from its former name GlaxoSmithKline plc) is a British Multinational corporation, multinational Pharmaceutics, pharmaceutical and biotechnology company with headquarters in London. It was established in 2000 by a Mergers an ...
's H1N1 flu vaccine
Pandemrix Pandemrix is an influenza vaccine for influenza pandemics, such as the 2009 flu pandemic. The vaccine was developed by GlaxoSmithKline (GSK) and patented in September 2006. The vaccine was one of the H1N1 vaccines approved for use by the Euro ...
and narcolepsy has been found in both children and adults. In 2010, Finland's National Institute of Health and Welfare recommended that Pandemrix vaccinations be suspended pending further investigation into narcolepsy. In 2018, it was demonstrated that T-cells stimulated by Pandemrix were cross-reactive by
molecular mimicry Molecular mimicry is the theoretical possibility that sequence similarities between foreign and self-peptides are enough to result in the cross-activation of autoreactive T or B cells by pathogen-derived peptides. Despite the prevalence of sever ...
with part of the hypocretin peptide, the loss of which is associated with type I narcolepsy.


Pathophysiology


Loss of neurons

Orexin, otherwise known as hypocretin, is a
neuropeptide Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the ...
that acts within the brain to regulate appetite and wakefulness as well as a number of other cognitive and physiological processes. Loss of these orexin-producing neurons causes narcolepsy, and most individuals with narcolepsy have a reduced number of these neurons in their brains. Selective destruction of the HCRT/OX neurons with preservation of proximate structures suggests a highly specific autoimmune pathophysiology. Text was copied from this source, which is available under
Creative Commons Attribution 4.0 International License
Cerebrospinal fluid HCRT-1/OX-A is undetectable in up to 95% of patients with type 1 narcolepsy. The system which regulates sleep, arousal, and transitions between these states in humans is composed of three interconnected subsystems: the
orexin Orexin (), also known as hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite. It exists in the forms of orexin-A and orexin-B. The most common form of narcolepsy, type 1, in which the individual experiences brief loss ...
projections from the
lateral hypothalamus The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cogni ...
, the
reticular activating system The reticular formation is a set of interconnected nuclei in the brainstem that spans from the lower end of the medulla oblongata to the upper end of the midbrain. The neurons of the reticular formation make up a complex set of neural networks ...
, and the
ventrolateral preoptic nucleus The ventrolateral preoptic nucleus (VLPO), also known as the intermediate nucleus of the preoptic area (IPA), is a small cluster of neurons situated in the anterior hypothalamus, sitting just above and to the side of the optic chiasm in the brai ...
. In narcoleptic individuals, these systems are all associated with impairments due to a greatly reduced number of hypothalamic orexin projection neurons and significantly fewer orexin neuropeptides in
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
and neural tissue, compared to non-narcoleptic individuals. Those with narcolepsy generally experience the
REM Rem or REM may refer to: Music * R.E.M., an American rock band * ''R.E.M.'' (EP), by the band Green * "R.E.M." (song), by Ariana Grande Science and technology * Rapid eye movement sleep, a phase of sleep * Roentgen equivalent man (rem), a unit ...
stage of sleep within five minutes of falling asleep, while people who do not have narcolepsy (unless they are significantly sleep deprived) do not experience REM until after a period of
slow-wave sleep Slow-wave sleep (SWS), often referred to as deep sleep, is the third stage of non-rapid eye movement sleep (NREM), where electroencephalography activity is characterised by slow delta waves. Slow-wave sleep usually lasts between 70 and 90 mi ...
, which lasts for about the first hour or so of a sleep cycle.


Disturbed sleep states

The neural control of normal sleep states and the relationship to narcolepsy are only partially understood. In humans, narcoleptic sleep is characterized by a tendency to go abruptly from a waking state to
REM sleep Rapid eye movement sleep (REM sleep or REMS) is a unique phase of sleep in mammals (including humans) and birds, characterized by random rapid movement of the eyes, accompanied by low muscle tone throughout the body, and the propensity of the s ...
with little or no intervening non-REM sleep. The changes in the motor and
proprioceptive Proprioception ( ) is the sense of self-movement, force, and body position. Proprioception is mediated by proprioceptors, a type of sensory receptor, located within muscles, tendons, and joints. Most animals possess multiple subtypes of propri ...
systems during REM sleep have been studied in both human and animal models. During normal REM sleep, spinal and brainstem
alpha motor neuron Alpha (α) motor neurons (also called alpha motoneurons), are large, multipolar neuron, multipolar lower motor neurons of the brainstem and spinal cord. They innervate extrafusal muscle fibers of skeletal muscle and are directly responsible for i ...
hyperpolarization produces almost complete
atonia This glossary of medical terms is a list of definitions about medicine, its sub-disciplines, and related fields. A * Aarskog–Scott syndrome – (AAS) A rare, inherited (X-linked) disease characterized by short stature, facial abnormalities, ...
of
skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...
s via an inhibitory descending reticulospinal pathway.
Acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...
may be one of the
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...
s involved in this pathway. In narcolepsy, the reflex inhibition of the motor system seen in
cataplexy Cataplexy is a sudden and transient episode of muscle weakness accompanied by full conscious awareness, typically triggered by emotions such as laughing, crying, or terror. Cataplexy is the first symptom to appear in about 10% of cases of narcol ...
has features normally seen only in normal REM sleep.


Diagnosis

The third edition of the
International Classification of Sleep Disorders The International Classification of Sleep Disorders (ICSD) is "a primary diagnostic, epidemiological and coding resource for clinicians and researchers in the field of sleep and sleep medicine". The ICSD was produced by the American Academy of Sle ...
(ICSD-3) differentiates between narcolepsy with cataplexy (type 1) and narcolepsy without cataplexy (type 2), while the fifth edition of the
Diagnostic and Statistical Manual of Mental Disorders The ''Diagnostic and Statistical Manual of Mental Disorders'' (''DSM''; latest edition: ''DSM-5-TR'', published in March 2022) is a publication by the American Psychiatric Association (APA) for the classification of mental disorders using a com ...
(DSM-5) uses the diagnosis of narcolepsy to refer to type 1 narcolepsy only. The DSM-5 refers to narcolepsy without cataplexy as hypersomnolence disorder. The most recent edition of the
International Classification of Diseases The International Classification of Diseases (ICD) is a globally used medical classification that is used in epidemiology, health management and clinical diagnosis. The ICD is maintained by the World Health Organization (WHO), which is the dir ...
, ICD-11, currently identifies three types of narcolepsy: type 1 narcolepsy, type 2 narcolepsy, and unspecified narcolepsy. ICSD-3 diagnostic criteria posit that the individual must experience "daily periods of irrepressible need to sleep or daytime lapses into sleep" for both subtypes of narcolepsy. This symptom must last for at least three months. For a diagnosis of type 1 narcolepsy, the person must present with either cataplexy, a mean
sleep latency In sleep science, sleep onset latency (SOL) is the length of time that it takes to accomplish the transition from full wakefulness to sleep, normally to the lightest of the non-REM sleep stages. Sleep latency studies Pioneering Stanford Univers ...
of less than 8 minutes, and two or more sleep-onset REM periods (SOREMPs), or they must present with a hypocretin-1 concentration of less than 110 pg/mL. A diagnosis of type 2 narcolepsy requires a mean sleep latency of less than 8 minutes, two or more SOREMPs, and a hypocretin-1 concentration of more than 110 pg/mL. In addition, the hypersomnolence and sleep latency findings cannot be better explained by other causes. DSM-5 narcolepsy criteria requires that the person to display recurrent periods of "an irrepressible need to sleep, lapsing into sleep, or napping" for at least three times a week over three months. The individual must also display one of the following: cataplexy, hypocretin-1 concentration of less than 110 pg/mL, REM sleep latency of less than 15 minutes, or a multiple sleep latency test (MSLT) showing sleep latency of less than 8 minutes and two or more SOREMPs. For a diagnosis of hypersomnolence disorder, the individual must present with excessive sleepiness despite at least 7 hours of sleep as well as either recurrent lapses into daytime sleep, nonrestorative sleep episodes of 9 or more hours, or difficulty staying awake after awakening. In addition, the hypersomnolence must occur at least three times a week for three months, and must be accompanied by significant distress or impairment. It also cannot be explained by another sleep disorder, coexisting mental or medical disorders, or medication.


Tests

Diagnosis is relatively easy when all the symptoms of narcolepsy are present, but if the sleep attacks are isolated and cataplexy is mild or absent, diagnosis is more difficult. Three tests that are commonly used in diagnosing narcolepsy are polysomnography (PSG), the multiple sleep latency test (MSLT), and the Epworth Sleepiness Scale (ESS). These tests are usually performed by a sleep specialist. Polysomnography involves the continuous recording of sleep brain waves and a number of nerve and muscle functions during nighttime sleep. When tested, people with narcolepsy fall asleep rapidly, enter REM sleep early, and may often awaken during the night. The polysomnogram also helps to detect other possible sleep disorders that could cause daytime sleepiness. The Epworth Sleepiness Scale is a brief questionnaire that is administered to determine the likelihood of the presence of a sleep disorder, including narcolepsy. The multiple sleep latency test is performed after the person undergoes an overnight sleep study. The person will be asked to sleep once every 2 hours, and the time it takes for them to do so is recorded. Most individuals will fall asleep within 5 to 8 minutes, as well as display REM sleep faster than non-narcoleptic people. Measuring orexin levels in a person's
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless Extracellular fluid#Transcellular fluid, transcellular body fluid found within the meninges, meningeal tissue that surrounds the vertebrate brain and spinal cord, and in the ventricular system, ven ...
sampled in a spinal tap may help in diagnosing narcolepsy, with abnormally low levels serving as an indicator of the disorder. This test can be useful when MSLT results are inconclusive or difficult to interpret.


Treatment


Orexin replacement

People with narcolepsy can be substantially helped, but not cured, currently. However, the technology exists in early form such as experiments in using the prepro-orexin transgene via gene editing restored normal function in mice models by making other neurons produce orexin after the original set have been destroyed, or replacing the missing orexinergic neurons with hypocretin stem cell transplantation, are both steps in that direction for fixing the biology effectively permanently once applied in humans. Additionally effective ideal non-gene editing and chemical-drug methods involve hypocretin treatments methods such as future drugs like hypocretin agonists (such as
danavorexton Danavorexton (developmental code name TAK-925) is a selective orexin 2 receptor agonist. It is a small-molecule compound and is administered intravenously. The compound was found to dose-dependently produce wakefulness to a similar degree as ...
) or hypocretin replacement, in the form of hypocretin 1 given
intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
(injected into the veins), intracisternal (direct injection into the brain), and
intranasal Nasal administration, popularly known as snorting, is a route of administration in which drugs are insufflation (medicine), insufflated through the nose. It can be a form of either topical administration or systemic administration, as the drugs t ...
(sprayed through the nose), the latter being low in efficacy, at the low amount used in current experiments but may be effective at very high doses in the future.


Behavioral

General strategies like people and family education, sleep hygiene, medication adherence, and discussion of safety issues, for example driving license, can be useful. Potential side effects of medication can also be addressed. Regular follow-up is useful to be able to monitor the response to treatment, to assess the presence of other sleep disorders like obstructive sleep apnea, and to discuss psychosocial issues. In many cases, planned regular short naps can reduce the need for pharmacological treatment of the EDS, but only improve symptoms for a short duration. A 120-minute nap provided benefit for 3  hours in the person's alertness whereas a 15-minute nap provided no benefit. Daytime naps are not a replacement for night time sleep. Ongoing communication between the health care provider, the person, and their family members is important for optimal management of narcolepsy.


Medications

As described above, medications used to treat narcolepsy primarily target EDS and/or cataplexy. Internationally, there are differences in the availability of medications as well as guidelines for treatment. The alerting agents are medications typically used to improve wakefulness and include
modafinil Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant and wakefulness-promoting agent, eugeroic (wakefulness promoter) medication used primarily to treat narcolepsy, a sleep disorder characteri ...
,
armodafinil Armodafinil, sold under the brand name Nuvigil, is a wakefulness-promoting medication which is used to treat excessive daytime sleepiness associated with obstructive sleep apnea, narcolepsy, and shift work disorder. It is also used off-label ...
,
pitolisant Pitolisant, sold under the brand name Wakix among others, is a medication used for the treatment of excessive daytime sleepiness in adults with narcolepsy. It is an inverse agonist of the histamine H3 receptor. It represents the first commerc ...
, and
solriamfetol Solriamfetol, sold under the brand name Sunosi, is a wakefulness-promoting medication used in the treatment of excessive sleepiness related to narcolepsy and sleep apnea. It is taken by mouth. Common side effects of solriamfetol include hea ...
. In late 2007, an alert for severe adverse skin reactions to modafinil was issued by the
FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
.
Solriamfetol Solriamfetol, sold under the brand name Sunosi, is a wakefulness-promoting medication used in the treatment of excessive sleepiness related to narcolepsy and sleep apnea. It is taken by mouth. Common side effects of solriamfetol include hea ...
is a new molecule indicated for narcolepsy of type 1 and 2. Solriamfetol works by inhibiting the reuptake of the monoamines via the interaction with both the dopamine transporter and the norepinephrine transporter. This mechanism differs from that of the wake-promoting agents modafinil and armodafinil. These are thought to bind primarily at the dopamine transporter to inhibit the reuptake of dopamine. Solriamfetol also differs from amphetamines as it does not promote the release of norepinephrine in the brain. Uniquely,
Pitolisant Pitolisant, sold under the brand name Wakix among others, is a medication used for the treatment of excessive daytime sleepiness in adults with narcolepsy. It is an inverse agonist of the histamine H3 receptor. It represents the first commerc ...
has a novel mechanism of action as an H3 antagonists, which promotes the release of the wakefulness-promoting molecule amine histamine. It was initially available in France, United Kingdom's (
NHS The National Health Service (NHS) is the term for the publicly funded health care, publicly funded healthcare systems of the United Kingdom: the National Health Service (England), NHS Scotland, NHS Wales, and Health and Social Care (Northern ...
) after being given marketing authorisation by European Commission on the advice of the
European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...
and then in the United States by the approval of the
Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...
(FDA) .
Pemoline Pemoline, formerly sold under the brand name Cylert among others, is a stimulant medication which was used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy,- it has since been discontinued in most countries due ...
was previously used but was withdrawn due to toxicity. Traditional stimulants, such as
methylphenidate Methylphenidate, sold under the brand names Ritalin ( ) and Concerta ( ) among others, is a central nervous system (CNS) stimulant used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It may be taken Oral adm ...
,
amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...
, and
dextroamphetamine Dextroamphetamine (international nonproprietary name, INN: dexamfetamine) is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narc ...
can be used, but are commonly considered second- or third-line therapy.
Sodium oxybate Sodium is a chemical element; it has symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable isotope ...
, also known as sodium gamma-hydroxybutyrate (GHB), can be used for
cataplexy Cataplexy is a sudden and transient episode of muscle weakness accompanied by full conscious awareness, typically triggered by emotions such as laughing, crying, or terror. Cataplexy is the first symptom to appear in about 10% of cases of narcol ...
associated with narcolepsy and excessive daytime sleepiness associated with narcolepsy. There are now three formulations of oxybate medications (twice-nightly
sodium oxybate Sodium is a chemical element; it has symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable isotope ...
, twice nightly mixed salts oxybate, and once-nightly extended-release sodium oxybate). This class of medication is taken once or twice during the night, as opposed to other medications for EDS and cataplexy that are typically taken during the day. Other medications that suppress REM sleep may also be used for the treatment of cataplexy as well as potentially other REM dissociative symptoms.
Tricyclic antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains ...
s (
clomipramine Clomipramine, sold under the brand name Anafranil among others, is a tricyclic antidepressant (TCA). It is used in the treatment of various conditions, most notably obsessive–compulsive disorder but also many other disorders, including hyper ...
,
imipramine Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression. It is also effective in treating anxiety and panic disorder. Imipramine is taken by mouth. Common s ...
, or
protriptyline Protriptyline, sold under the brand name Vivactil among others, is a tricyclic antidepressant (TCA), specifically a secondary amine. Uniquely among most of the TCAs, protriptyline tends to be energizing instead of sedating, and is sometimes use ...
),
selective serotonin reuptake inhibitor Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by blo ...
s (SSRIs), and selective norepinephrine reuptake inhibitors (SNRIs) (
Venlafaxine Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin–norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, pani ...
) are used for the treatment of cataplexy.
Atomoxetine Atomoxetine, formerly sold under the brand name Strattera, is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndr ...
, a non-stimulant and a
norepinephrine reuptake inhibitor A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinep ...
(NRI), which has no addiction liability or recreational effects, has been used with variable benefit. Other NRIs like
viloxazine Viloxazine, sold under the brand name Qelbree among others, is a selective norepinephrine reuptake inhibitor medication that is indicated in the treatment of attention deficit hyperactivity disorder (ADHD) in children and adults. It was market ...
and
reboxetine Reboxetine, sold under the brand name Edronax among others, is a selective norepinephrine reuptake inhibitor (sNRI) medication marketed as an antidepressant by Pfizer for use in the treatment of major depressive disorder, although it has also be ...
have also been used in the treatment of narcolepsy. Additional related medications include
mazindol Mazindol, sold under the brand names Mazanor and Sanorex, is a central nervous system (CNS) stimulant which is used as an appetite suppressant. It was developed by Sandoz Laboratories, Sandoz-Wander in the 1960s. The US Food and Drug Administrat ...
and
selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Zelapar, and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It has also been studied and us ...
.


Children

Common behavioral treatments for childhood narcolepsy include improved sleep hygiene, scheduled naps, and physical exercise. Many medications are used to treat adults and may be used to treat children. These medications include central nervous system stimulants such as methylphenidate, modafinil, amphetamine, and dextroamphetamine. Other medications, such as
sodium oxybate Sodium is a chemical element; it has symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable isotope ...
or
atomoxetine Atomoxetine, formerly sold under the brand name Strattera, is a selective norepinephrine reuptake inhibitor (sNRI) medication used to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, cognitive disengagement syndr ...
, may also be used to counteract sleepiness. Medications such as sodium oxybate,
venlafaxine Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin–norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, pani ...
,
fluoxetine Fluoxetine, sold under the brand name Prozac, among others, is an Antidepressant, antidepressant medication of the selective serotonin reuptake inhibitor (SSRI) class used for the treatment of major depressive disorder, Anxiety disorder, anx ...
, and
clomipramine Clomipramine, sold under the brand name Anafranil among others, is a tricyclic antidepressant (TCA). It is used in the treatment of various conditions, most notably obsessive–compulsive disorder but also many other disorders, including hyper ...
may be prescribed if the child presents with cataplexy.


Epidemiology

Estimates of frequency range from 0.2 per 100,000 in Israel to 600 per 100,000 in Japan. These differences may be due to how the studies were conducted or the populations themselves. In the
United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...
, narcolepsy is estimated to affect as many as 200,000 Americans, but fewer than 50,000 are diagnosed. The prevalence of narcolepsy is about 1 per 2,000 persons. Narcolepsy is often mistaken for depression,
epilepsy Epilepsy is a group of Non-communicable disease, non-communicable Neurological disorder, neurological disorders characterized by a tendency for recurrent, unprovoked Seizure, seizures. A seizure is a sudden burst of abnormal electrical activit ...
, the
side effects In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects. A drug or procedure usually used ...
of medications, poor sleeping habits or
recreational drug use Recreational drug use is the use of one or more psychoactive drugs to induce an altered state of consciousness, either for pleasure or for some other casual purpose or pastime. When a psychoactive drug enters the user's body, it induces an Sub ...
, making misdiagnosis likely. While narcolepsy symptoms are often confused with depression, there is a link between the two disorders. Research studies have mixed results on co-occurrence of depression in people with narcolepsy, as the numbers quoted by different studies are anywhere between 6% and 50%. Narcolepsy can occur in both men and women at any age, although typical symptom onset occurs in
adolescence Adolescence () is a transitional stage of human Developmental biology, physical and psychological Human development (biology), development that generally occurs during the period from puberty to adulthood (typically corresponding to the age o ...
and young adulthood. There is about a ten-year delay in diagnosing narcolepsy in adults. Cognitive, educational, occupational, and psychosocial problems associated with the excessive daytime sleepiness of narcolepsy have been documented. For these to occur in the crucial teen years, when education, development of self-image, and development of occupational choice are taking place, is especially devastating. While cognitive impairment does occur, it may only be a reflection of the excessive daytime somnolence.


Society and culture

In 2015, it was reported that the British
Department of Health A health department or health ministry is a part of government which focuses on issues related to the general health of the citizenry. Subnational entities, such as states, counties and cities, often also operate a health department of their o ...
was paying for
sodium oxybate Sodium is a chemical element; it has symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 of the periodic table. Its only stable isotope ...
medication at a cost of £12,000 a year for 80 people who are taking legal action over problems linked to the use of the
Pandemrix Pandemrix is an influenza vaccine for influenza pandemics, such as the 2009 flu pandemic. The vaccine was developed by GlaxoSmithKline (GSK) and patented in September 2006. The vaccine was one of the H1N1 vaccines approved for use by the Euro ...
swine flu vaccine. Sodium oxybate is not available to people with narcolepsy through the
National Health Service The National Health Service (NHS) is the term for the publicly funded health care, publicly funded healthcare systems of the United Kingdom: the National Health Service (England), NHS Scotland, NHS Wales, and Health and Social Care (Northern ...
.


Name

The term "narcolepsy" is from the French ''narcolepsie''. The French term was first used in 1880 by
Jean-Baptiste-Édouard Gélineau Jean-Baptiste-Édouard Gélineau (23 December 1828 – 2 March 1906) was the French physician and Neuropsychiatry, neuropsychiatrist who first described narcolepsy. Early life and education Gélineau was born in Blaye, Gironde, and had a varied ...
, who used the
Greek Greek may refer to: Anything of, from, or related to Greece, a country in Southern Europe: *Greeks, an ethnic group *Greek language, a branch of the Indo-European language family **Proto-Greek language, the assumed last common ancestor of all kno ...
νάρκη (''narkē''), meaning "numbness", and λῆψις (''lepsis'') meaning "attack".


Research


GABA-directed medications

Given the possible role of hyperactive
GABA GABA (gamma-aminobutyric acid, γ-aminobutyric acid) is the chief inhibitory neurotransmitter in the developmentally mature mammalian central nervous system. Its principal role is reducing neuronal excitability throughout the nervous system. GA ...
A receptors in the primary hypersomnias (narcolepsy and idiopathic hypersomnia), medications that could counteract this activity are being studied to test their potential to improve sleepiness. These currently include
clarithromycin Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, '' H. pylori'' infection, and Lyme disease, among others. Clari ...
and
flumazenil Flumazenil, also known as flumazepil, is a selective GABAA receptor, GABAA receptor antagonist administered via injection, otic insertion, or intranasally. Therapeutically, it acts as both an antagonist and antidote to benzodiazepines (partic ...
.


Flumazenil

Flumazenil is the only GABAA receptor antagonist on the market as of January 2013, and it is currently manufactured only as an intravenous formulation. Given its pharmacology, researchers consider it a promising medication in the treatment of primary hypersomnias. Results of a small, double-blind, randomized, controlled clinical trial were published in November 2012. This research showed that flumazenil provides relief for most people whose CSF contains the unknown "somnogen" that enhances the function of GABAA receptors, making them more susceptible to the sleep-inducing effect of GABA. For one person, daily administration of flumazenil by sublingual lozenge and topical cream has proven effective for several years. A 2014 case report also showed improvement in primary hypersomnia symptoms after treatment with a continuous subcutaneous flumazenil infusion. The supply of generic flumazenil was initially thought to be too low to meet the potential demand for treatment of primary hypersomnias. However, this scarcity has eased, and dozens of people are now being treated with flumazenil off-label.


Clarithromycin

In a test tube model,
clarithromycin Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, '' H. pylori'' infection, and Lyme disease, among others. Clari ...
(an antibiotic approved by the FDA for the treatment of infections) was found to return the function of the GABA system to normal in people with primary hypersomnias. Investigators, therefore, treated a few people with narcolepsy with off-label clarithromycin, and most felt their symptoms improved with this treatment. To help further determine whether clarithromycin is truly beneficial for the treatment of narcolepsy and idiopathic hypersomnia, a small, double-blind, randomized, controlled clinical trial was completed in 2012. "In this pilot study, clarithromycin improved subjective sleepiness in GABA-related hypersomnia. Larger trials of longer duration are warranted." In 2013, a retrospective review evaluating longer-term clarithromycin use showed efficacy in a large percentage of people with GABA-related hypersomnia. "It is important to note that the positive effect of clarithromycin is secondary to a
benzodiazepine Benzodiazepines (BZD, BDZ, BZs), colloquially known as "benzos", are a class of central nervous system (CNS) depressant, depressant drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They are prescribed t ...
antagonist-like effect, not its antibiotic effects, and treatment must be maintained."


Orexin receptor agonists

Orexin-A Orexin-A, also known as hypocretin-1, is a naturally occurring neuropeptide and orexin isoform. The orexinergic nucleus in the lateral hypothalamus is the primary orexin projection system in the brain. Structure Orexin-A is a peptide composed of ...
( hypocretin-1) is strongly wake-promoting in animal models, but it does not cross the
blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...
. The first-line treatment for narcolepsy,
modafinil Modafinil, sold under the brand name Provigil among others, is a central nervous system (CNS) stimulant and wakefulness-promoting agent, eugeroic (wakefulness promoter) medication used primarily to treat narcolepsy, a sleep disorder characteri ...
, has been found to interact indirectly with the orexin system. It is also likely that an
orexin receptor The orexin receptor (also referred to as the hypocretin receptor) is a G-protein-coupled receptor that binds the neuropeptide orexin. There are two variants, OX1 and OX2, each encoded by a different gene (, ). Both orexin receptors exhibit ...
agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...
will be found and developed for the treatment of hypersomnia. One such agent which is currently in clinical trials is
danavorexton Danavorexton (developmental code name TAK-925) is a selective orexin 2 receptor agonist. It is a small-molecule compound and is administered intravenously. The compound was found to dose-dependently produce wakefulness to a similar degree as ...
.


L-carnitine

Abnormally low levels of
acylcarnitine Carnitine is a quaternary ammonium compound involved in metabolism in most mammals, plants, and some bacteria. In support of energy metabolism, carnitine transports long-chain fatty acids from the cytosol into Mitochondrion, mitochondria to be R ...
have been observed in people with narcolepsy. These same low levels have been associated with primary hypersomnia in general in mouse studies. "Mice with systemic carnitine deficiency exhibit a higher frequency of fragmented wakefulness and rapid eye movement (REM) sleep, and reduced locomotor activity." Administration of
acetyl-L-carnitine Acetyl-L-carnitine, ALCAR or ALC, is an acetylated form of L-carnitine. It is naturally produced by the human body, and it is available as a dietary supplement. Acetylcarnitine is broken down in the blood by plasma esterases to carnitine which ...
was shown to improve these symptoms in mice. A subsequent human trial found that people with narcolepsy given L-carnitine spent less total time in daytime sleep than people who were given a placebo.


Animal models

Animal studies try to mimic the disorder in humans by either modifying the Hypocretin/Orexin receptors or by eliminating this peptide. An orexin deficit caused by the degeneration of hypothalamic neurons is suggested to be one of the causes of narcolepsy. More recent clinical studies on both animals and humans have also revealed that hypocretin is involved in other functions beside regulation of wakefulness and sleep. These functions include autonomic regulation, emotional processing, reward learning behaviour and energy homeostasis. In studies where the concentration of the hypocretin was measured under different circumstances, it was observed that the hypocretin levels increased with positive emotion, anger, or social interaction, but stayed low during sleep or pain experience. The most reliable and valid animal models developed are the canine (narcoleptic dogs) and the rodent (orexin-deficient mice) ones, which helped investigate the narcolepsy and set the focus on the role of orexin in this disorder.


Dog models

Dogs, as well as other species like cats or horses, can also exhibit spontaneous narcolepsy with similar symptoms to those reported in humans. The attacks of cataplexy in dogs can involve partial or full collapse. Narcolepsy with cataplexy was identified in a few breeds like Labrador retrievers or Doberman pinschers, where it was investigated the possibility of inheriting this disorder in an autosomal recessive mode. According to a reliable canine model for narcolepsy would be the one in which the narcoleptic symptoms are the result of a mutation in the gene HCRT 2. The animals affected exhibited excessive daytime sleepiness with a reduced state of vigilance and severe cataplexy resulting from palatable food and interactions with the owners or with other animals.


Rodent models

Mice that are genetically engineered to lack orexin genes demonstrate many similarities to human narcolepsy. During nocturnal hours, when mice are normally present, those lacking orexin demonstrated
murine The Old World rats and mice, part of the subfamily Murinae in the family Muridae, comprise at least 519 species. Members of this subfamily are called murines. In terms of species richness, this subfamily is larger than all mammal families excep ...
cataplexy and displayed brain and muscle electrical activity similar to the activity present during REM and NREM sleep. This cataplexy can be triggered through social interaction, wheel running, and ultrasonic vocalizations. Upon awakening, the mice also display behavior consistent with excessive daytime sleepiness. Mouse models have also been used to test whether the lack of orexin
neuron A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s is correlated with narcolepsy. Mice whose orexin neurons have been ablated have shown sleep fragmentation, SOREMPs, and obesity. Rat models have been used to demonstrate the association between orexin deficiency and narcoleptic symptoms. Rats that lost the majority of their orexinergic neurons exhibited multiple SOREMPs as well as less wakefulness during nocturnal hours, shortened REM latency, and brief periods of cataplexy.


References


External links

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European Sleep Research Society (ESRS)
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